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  • Title: Polymers for nucleic acid transfer-an overview.
    Author: Wagner E.
    Journal: Adv Genet; 2014; 88():231-61. PubMed ID: 25409608.
    Abstract:
    For the last five decades cationic polymers have been used for nucleic acids transfection. Our understanding of polymer-nucleic acid interactions and their rational use in delivery has continuously increased. The great improvements in macromolecular chemistry and the recognition of distinct biological extra- and intracellular delivery hurdles triggered several breakthrough developments, including the discovery of natural and synthetic polycations for compaction of nucleic acids into stable nanoparticles termed polyplexes; the incorporation of targeting ligands and surface-shielding of polyplexes to enable receptor-mediated gene delivery into defined target tissues; and strongly improved intracellular transfer efficacy by better endosomal escape of vesicle-trapped polyplexes into the cytosol. These experiences triggered the development of second-generation polymers with more dynamic properties, such as endosomal pH-responsive release mechanisms, or biodegradable units for improved biocompatibility and intracellular release of the nucleic acid pay load. Despite a better biological understanding, significant challenges such as efficient nuclear delivery and persistence of gene expression persist. The therapeutic perspectives widened from pDNA-based gene therapy to application of novel therapeutic nucleic acids including mRNA, siRNA, and microRNA. The finding that different therapeutic pay loads require different tailor-made carriers complicates preclinical developments. Convincing evidence of medical efficacy still remains to be demonstrated. Bioinspired multifunctional polyplexes resembling "synthetic viruses" appear as attractive opportunity, but provide additional challenges: how to identify optimum combinations of functional delivery units, and how to prepare such polyplexes reproducibly in precise form? Design of sequence-defined polymers, screening of combinatorial polymer and polyplex libraries are tools for further chemical evolution of polyplexes.
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